The aims of this proposal are (1) to characterize further in quantitative terms the role of branched-chain ketoacids (BCKA) relative to branched- chain amino acids (BCAA) as precursors of protein and of CO2. The fractions of tracer doses of BCKA or BCAA incorporated into protein, f and F, and oxidized to CO2, 1-f and 1-F, are measured and results are expressed in terms of the ration f/F in whole body protein or in specific proteins and the ration (1-f)/(1-F) in expired CO2. We have shown these ratios to be time-independent (under certain conditions). We will determine in normal man the contribution of extracellular BCKA, relative to extracellular BCAA, to the synthesis of whole body protein, albumin, fibrin, globin, and salivary mucin, and also first pass oxidation of these compounds. (2) In rats fed parenterally, we find that 2-ketoisocaproate (KIC) spares N markedly. To see if suppression of glucocorticoid levels ( which we find to exert a profound effect on protein turnover) is responsible, we will repeat these experiments in hormone-replaced adrenalectomized rats, will see if long-term N-sparing occurs and involves suppression of glucorticoid production in normal rats, and will see if glucorticoid levels fall in KIC-infused fasting obese volunteers. (3) We propose that whole body protein synthesis, S, is more reliably measured from C, total amino acid catabolism, and 1-F [as C(F/(1-F)] than from plasma KIC enrichment (during labelled leucine infusion), that the fractions of total flux (Qi) of six amino acids (BCAA, lysine, methionine, and tryptophan) going to oxidation (Ci/Qi) and to protein synthesis (Si/Qi) tend to be equal, and that therefore BCKA oxi-dation must be proportionate to C except (1) when intake of these amino acids is disproportionate to relative Si values, or (2) when the ratio of free essential amino N to free non-essential N changes. We will test this hypothesis in rats, first by determining whether fractional oxidation rates of these six amino acids are indeed equal during fasting, and second by determining how fractional oxidation rates respond to infusing (or omitting from an otherwise balanced mixture) one of these amino acids.